Effects of Fatty Acid Metabolites on Adipocytes Britening: Role of Thromboxane A2.

Obesity is a complex disease highly related to diet and lifestyle and is associated with low amount of thermogenic adipocytes. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to fight overweight and associated comorbidities. Recent studies suggest a role for several fatty acids and their metabolites, called lipokines, in the control of thermogenesis. The purpose of this work was to analyze the role of several lipokines in the control of brown/brite adipocyte formation. We used a validated human adipocyte model, human multipotent adipose-derived stem cell model (hMADS). In the absence of rosiglitazone, hMADS cells differentiate into white adipocytes, but convert into brite adipocytes upon rosiglitazone or prostacyclin 2 (PGI2) treatment. Gene expression was quantified using RT-qPCR and protein levels were assessed by Western blotting. We show here that lipokines such as 12,13-diHOME, 12-HEPE, 15dPGJ2 and 15dPGJ3 were not able to induce browning of white hMADS adipocytes. However, both fatty acid esters of hydroxy fatty acids (FAHFAs), 9-PAHPA and 9-PAHSA potentiated brown key marker UCP1 mRNA levels. Interestingly, CTA2, the stable analog of thromboxane A2 (TXA2), but not its inactive metabolite TXB2, inhibited the rosiglitazone and PGI2-induced browning of hMADS adipocytes. These results pinpoint TXA2 as a lipokine inhibiting brown adipocyte formation that is antagonized by PGI2. Our data open new horizons in the development of potential therapies based on the control of thromboxane A2/prostacyclin balance to combat obesity and associated metabolic disorders.

Appetitive Motivation and Associated Neurobiology Change Differentially across the Life Course of Mouse Offspring Exposed to Peri- and Postnatal High Fat Feeding.

Alterations in neural pathways that regulate appetitive motivation may contribute to increased obesity risk in offspring born to mothers fed a high fat (HF) diet. However, current findings on the impact of maternal obesity on motivation in offspring are inconclusive, and there is no information about the long-lasting effects in aged animals. This study examined the longitudinal effect of perinatal and chronic postnatal HF intake on appetitive motivation in young and aged offspring. Female C57Bl/6 were fed either a control (C) or HF diet before mating through to lactation. At weaning, offspring were maintained on the C or HF diet, generating the following four diet groups: C/C, C/HF, HF/C, and HF/HF based on the pre/post weaning diet. At 6 months, motivation was higher in HF/C females, but lower in male and female C/HF and HF/HF mice. By 12 months, this difference was lost, as C-fed animals became less motivated, while motivation increased in HF-fed mice. The mRNA levels of dopamine receptor 1 and 2 increased with age, while cannabinoid receptor 1 and µ-opioid receptor expression remained stable or decreased in mesolimbic and mesocortical dopaminergic pathways. Results from this study suggest that perinatal and chronic postnatal HF feeding produced opposite effects on appetitive motivation in young adult offspring mice, which was also reflected in the shift in motivation over time. These results have significant implications for patterns of hedonic eating across the life course and the relative risk of obesity at different time points.

Inferior Vena Cava Edge Tracking Echocardiography: A Promising Tool with Applications in Multiple Clinical Settings.

Ultrasound (US)-based measurements of the inferior vena cava (IVC) diameter are widely used to estimate right atrial pressure (RAP) in a variety of clinical settings. However, the correlation with invasively measured RAP along with the reproducibility of US-based IVC measurements is modest at best. In the present manuscript, we discuss the limitations of the current technique to estimate RAP through IVC US assessment and present a new promising tool developed by our research group, the automated IVC edge-to-edge tracking system, which has the potential to improve RAP assessment by transforming the current categorical classification (low, normal, high RAP) in a continuous and precise RAP estimation technique. Finally, we critically evaluate all the clinical settings in which this new tool could improve current practice.

Pre- and Post-natal High Fat Feeding Differentially Affects the Structure and Integrity of the Neurovascular Unit of 16-Month Old Male and Female Mice.

Compelling experimental and clinical evidence supports a role for maternal obesity in offspring health. Adult children of obese mothers are at greater risk of obesity, diabetes, coronary heart disease and stroke. These offspring may also be at greater risk of age-related neurodegenerative diseases for which mid-life obesity is a risk factor. Rodent diet-induced obesity models have shown that high fat (HF) diet consumption damages the integrity of the blood-brain barrier (BBB) in the adult brain. However, there is currently little information about the effect of chronic HF feeding on the BBB of aged animals. Moreover, the long-term consequences of maternal obesity on the cerebrovasculature of aged offspring are not known. This study determined the impact of pre- and post-natal HF diet on the structure and integrity of cerebral blood vessels in aged male and female mice. Female C57Bl/6 mice were fed either a 10% fat control (C) or 45% HF diet before mating and during gestation and lactation. At weaning, male and female offspring were fed the C or HF diet until sacrifice at 16-months of age. Both dams and offspring fed the HF diet weighed significantly more than mice fed the C diet. Post-natal HF diet exposure increased hippocampal BBB leakiness in female offspring, in association with loss of astrocyte endfoot coverage of arteries. Markers of tight junctions, pericytes or smooth muscle cells were not altered by pre- or post-natal HF diet. Male offspring born to HF-fed mothers showed decreased parenchymal GFAP expression compared to offspring of mothers fed C diet, while microglial and macrophage markers were higher in the same female diet group. In addition, female offspring exposed to the HF diet for their entire lifespan showed more significant changes in vessel structure, BBB permeability and inflammation compared to male animals. These results suggest that the long-term impact of prenatal HF diet on the integrity of cerebral blood vessels differs between male and female offspring depending on the post-natal diet. This may have implications for the prevention and management of age- and obesity-related cerebrovascular diseases that differentially affect men and women.

Heroin versus cocaine: opposite choice as a function of context but not of drug history in the rat.

RATIONALE: Previous studies have shown that rats trained to self-administer heroin and cocaine exhibit opposite preferences, as a function of setting, when tested in a choice paradigm. Rats tested at home prefer heroin to cocaine, whereas rats tested outside the home prefer cocaine to heroin. Here, we investigated whether drug history would influence subsequent drug preference in distinct settings. Based on a theoretical model of drug-setting interaction, we predicted that regardless of drug history rats would prefer heroin at home and cocaine outside the home. METHODS: Rats with double-lumen catheters were first trained to self-administer either heroin (25 µg/kg) or cocaine (400 µg/kg) for 12 consecutive sessions. Twenty-six rats were housed in the self-administration chambers (thus, they were tested at home), whereas 30 rats lived in distinct home cages and were transferred to self-administration chambers only for the self-administration session (thus, they were tested outside the home). The rats were then allowed to choose repeatedly between heroin and cocaine within the same session for seven sessions. RESULTS: Regardless of the training drug, the rats tested outside the home preferred cocaine to heroin, whereas the rats tested at home preferred heroin to cocaine. There was no correlation between drug preference and drug intake during the training phase. CONCLUSION: Drug preferences were powerfully influenced by the setting but, quite surprisingly, not by drug history. This suggests that, under certain conditions, associative learning processes and drug-induced neuroplastic adaptations play a minor role in shaping individual preferences for one drug or the other.

Echocardiographic reference ranges for normal left atrial function parameters: results from the EACVI NORRE study.

Aims: To obtain the normal ranges for echocardiographic measurements of left atrial (LA) function from a large group of healthy volunteers accounting for age and gender. Methods and results: A total of 371 (median age 45 years) healthy subjects were enrolled at 22 collaborating institutions collaborating in the Normal Reference Ranges for Echocardiography (NORRE) study of the European Association of Cardiovascular Imaging (EACVI). Left atrial data sets were analysed with a vendor-independent software (VIS) package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire data sets. The lowest expected values of LA function were 26.1%, 48.7%, and 41.4% for left atrial strain (LAS), 2D left atrial emptying fraction (LAEF), and 3D LAEF (reservoir function); 7.7%, 24.2%, and -0.53/s for LAS-active, LAEF-active, and LA strain rate during LA contraction (SRa) (pump function) and 12.0% and 21.6% for LAS-passive and LAEF-passive (conduit function). Left atrial reservoir and conduit function were decreased with age while pump function was increased. All indices of reservoir function and all LA strains had no difference in both gender and vendor. However, inter-vendor differences were observed in LA SRa despite the use of VIS. Conclusion: The NORRE study provides contemporary, applicable echocardiographic reference ranges for LA function. Our data highlight the importance of age-specific reference values for LA functions.

What Does 3D Echocardiography Add to 2D Echocardiography in the Assessment of Mitral Regurgitation?

PURPOSE OF REVIEW: The purpose of this review was to elucidate the additional value of 3D echocardiography for the assessment of mitral regurgitation (MR) compared to standard 2D echocardiography. RECENT FINDINGS: 3D echocardiography provides key information, aetiology, degenerative mitral valve disease vs. secondary MR, causes and mechanism, severity by measurements of effective regurgitant orifice area and regurgitant volume; likelihood of reparability and assessment of pre- and intra-mitral valve transcatheter procedures. 3D echocardiography as a promising method for assessment of MR is useful and crucial for research, clinical practice and patient management in all heart valve team members.

Echocardiographic reference ranges for normal left ventricular 2D strain: results from the EACVI NORRE study.

AIMS: To obtain the normal ranges for 2D echocardiographic (2DE) measurements of left ventricular (LV) strain from a large group of healthy volunteers accounting for age and gender. METHODS AND RESULTS: A total of 549 (mean age: 45.6 ± 13.3 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. 2DE data sets have been analysed with a vendor-independent software package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire the data sets. The lowest expected values of LV strains and twist calculated as ± 1.96 standard deviations from the mean were -16.7% in men and -17.8% in women for longitudinal strain, -22.3% and -23.6% for circumferential strain, 20.6% and 21.5% for radial strain, and 2.2 degrees and 1.9 degrees for twist, respectively. In multivariable analysis, longitudinal strain decreased with age whereas the opposite occurred with circumferential and radial strain. Male gender was associated with lower strain for longitudinal, circumferential, and radial strain. Inter-vendor differences were observed for circumferential and radial strain despite the use of vendor-independent software. Importantly, no intervendor differences were noted in longitudinal strain. CONCLUSION: The NORRE study provides contemporary, applicable 2D echocardiographic reference ranges for LV longitudinal, radial, and circumferential strain. Our data highlight the importance of age- and gender-specific reference values for LV strain.

A Review of the Impact of Maternal Obesity on the Cognitive Function and Mental Health of the Offspring.

Globally, more than 20% of women of reproductive age are currently estimated to be obese. Children born to obese mothers are at higher risk of developing obesity, coronary heart disease, diabetes, stroke, and asthma in adulthood. Increasing clinical and experimental evidence suggests that maternal obesity also affects the health and function of the offspring brain across the lifespan. This review summarizes the current findings from human and animal studies that detail the impact of maternal obesity on aspects of learning, memory, motivation, affective disorders, attention-deficit hyperactivity disorder, autism spectrum disorders, and neurodegeneration in the offspring. Epigenetic mechanisms that may contribute to this mother-child interaction are also discussed.

Ultrasonic vocalization in rats self-administering heroin and cocaine in different settings: evidence of substance-specific interactions between drug and setting.

RATIONALE: Clinical and preclinical evidence indicates that the setting of drug use affects drug reward in a substance-specific manner. Heroin and cocaine co-abusers, for example, indicated distinct settings for the two drugs: heroin being used preferentially at home and cocaine preferentially outside the home. Similar results were obtained in rats that were given the opportunity to self-administer intravenously both heroin and cocaine. OBJECTIVES: The goal of the present study was to investigate the possibility that the positive affective state induced by cocaine is enhanced when the drug is taken at home relative to a non-home environment, and vice versa for heroin. METHODS: To test this hypothesis, we trained male rats to self-administer both heroin and cocaine on alternate days and simultaneously recorded the emission of ultrasonic vocalizations (USVs), as it has been reported that rats emit 50-kHz USVs when exposed to rewarding stimuli, suggesting that these USVs reflect positive affective states. RESULTS: We found that Non-Resident rats emitted more 50-kHz USVs when they self-administered cocaine than when self-administered heroin whereas Resident rats emitted more 50-kHz USVs when self-administering heroin than when self-administering cocaine. Differences in USVs in Non-Resident rats were more pronounced during the first self-administration (SA) session, when the SA chambers were completely novel to them. In contrast, the differences in USVs in Resident rats were more pronounced during the last SA sessions. CONCLUSION: These findings indicate that the setting of drug taking exerts a substance-specific influence on the ability of drugs to induce positive affective states.

Differential vulnerability to relapse into heroin versus cocaine-seeking as a function of setting.

RATIONALE: Previous studies have shown that the effect of setting on drug-taking is substance specific in both humans and rats. In particular, we have shown that when the setting of drug self-administration (SA) coincides with the home environment of the rats (resident rats), the rats tend to prefer heroin to cocaine. The opposite was found in nonresident rats, for which the SA chambers represented a distinct environment. OBJECTIVES: The aim of the present study was to investigate the influence of setting on the ability of different doses of cocaine and heroin to prime cocaine- versus heroin-seeking in rats that had been trained to self-administer both drugs and had then undergone an extinction procedure. METHODS: Resident (N = 62) and nonresident (N = 63) rats with double-lumen intra-jugular catheters were trained to self-administer cocaine (400 µg/kg/infusion) and heroin (25 µg/kg/infusion) on alternate days for 10 consecutive daily sessions (3 h each). After the extinction phase, independent groups of rats were given a noncontingent intravenous infusion of heroin (25, 50, or 100 µg/kg) or cocaine (400, 800, or 1600 µg/kg), and drug-seeking was quantified by counting nonreinforced lever presses. RESULTS: All resident and nonresident rats acquired heroin and cocaine SA. However, cocaine primings reinstated cocaine-seeking only in nonresident rats, whereas heroin primings reinstated heroin-seeking only in resident rats. CONCLUSIONS: We report here that the susceptibility to relapse into drug-seeking behavior is drug-specific and setting-specific, confirming the crucial role played by drug, set, and setting interactions in drug addiction.